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Updated: Oct 16, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification of an AXL kinase inhibitor in triple-negative breast cancer by structure-based virtual screening and
Pei Li1,2, Yuzhen Niu3, Shuyan Li4
1The First Affiliated Hospital, Department of Oncology, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Abstract:
Breast cancer is a malignant tumor that occurs in the glandular epithelium of the breast, and more than 15% of the patients are triple-negative breast cancer (TNBC). Therefore, finding new targets and targeted therapeutic drugs for TNBC is urgent. Overexpression of the AXL is associated with motility and invasiveness of the TNBC cells, which is a potential target for breast cancer therapy. A compound Y041-5921 (IC50 = 6.069 μm for AXL kinase and IC50 = 4.1 μm for MDA-MB-231 cell line) was identified through structure-based virtual screening and bioassay test for the first time. The compound Y041-5921 could significantly inhibit the proliferation and invasion of the TNBC cells and the toxicity of Y041-5921 to normal immortalized breast epithelial cells was far lower than that of commonly used clinical chemotherapy drugs. Besides, it also had well inhibitory effect on the proliferation of many other malignant tumor cell lines (the IC50 value are 10.0 m, 7.1 m, 10.3 m, 11.4 m and 5.8 m for U251 cell, COLO cell, PC-9 cell, CAKI-1 cell and MG63 cell, respectively). The interaction mechanism between Y041-5921 and AXL was studied by molecular dynamics (MD) simulations and binding free energy calculation, and the key residues whose energy contribution mainly comes from non-polar solvation interaction (such as Ala565, Lys567, Met598, Leu620, Pro621, Met623, Lys624, Arg676, Asn677 and Met679) were identified. The small molecule inhibitors Y041-5921 targeting AXL reported in this work will lay a foundation and provide a theoretical basis for the development of the TNBC.
Insights
A new compound, Y041-5921, effectively inhibits triple-negative breast cancer (TNBC) cell proliferation and invasion by targeting the AXL receptor. This promising drug candidate shows lower toxicity to normal cells compared to traditional chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) accounts for over 15% of breast cancer cases, necessitating urgent development of targeted therapies.
- Overexpression of the AXL receptor tyrosine kinase is linked to increased motility and invasiveness in TNBC cells, identifying it as a potential therapeutic target.
Purpose of the Study:
- To identify and characterize novel small molecule inhibitors targeting AXL for the treatment of TNBC.
- To evaluate the efficacy and safety profile of the identified compound Y041-5921 against TNBC cells and normal breast epithelial cells.
Main Methods:
- Structure-based virtual screening and bioassay were employed to discover the AXL inhibitor Y041-5921.
- In vitro assays assessed the compound's inhibitory effects on TNBC cell proliferation and invasion.
- Molecular dynamics (MD) simulations and binding free energy calculations were used to elucidate the interaction mechanism between Y041-5921 and AXL.
Main Results:
- The compound Y041-5921 was identified as a potent inhibitor of AXL kinase (IC50 = 6.069 μm) and MDA-MB-231 TNBC cells (IC50 = 4.1 μm).
- Y041-5921 significantly inhibited TNBC cell proliferation and invasion with notably lower toxicity to normal breast epithelial cells compared to standard chemotherapy drugs.
- The compound demonstrated inhibitory effects against various other malignant tumor cell lines, including U251, COLO, PC-9, CAKI-1, and MG63 cells.
Conclusions:
- The novel small molecule Y041-5921 effectively targets AXL and exhibits significant anti-TNBC activity.
- Y041-5921 represents a promising therapeutic candidate for TNBC, offering a potentially safer alternative to existing chemotherapy.
- This study provides a foundation for the development of AXL-targeted therapies for TNBC and other cancers.
